Abstract Body (Do not enter title and authors here): Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a leading cause of morbidity and mortality despite current therapies. The transverse aortic constriction (TAC) model in rodent mimics conditions such as hypertension and aortic stenosis and is widely used to study HFrEF. SGK1, a stress activated kinase, plays a key role in cardiac remodeling, fibrosis, and inflammation, critical in HF progression. Genetic inhibition of SGK1 by cardiac-specific expression of dominant-negative SGK1 in a TAC model is shown to be cardioprotective. Small molecule inhibitors of SGK1 (SGK1i) have not previously been evaluated in the TAC model.

Research Questions: To evaluate the efficacy of novel, potent and selective SGK1i in a TAC model.

Methods: Male, Sprague Dawley Rats, that had undergone TAC (20G suture) or sham surgery were dosed once a day via oral gavage from Day 3 until the end of the study on Day 56 with vehicle, SGK1i A, or SGK1i B. All animals had echocardiography on Days 21, 28, 42 and 56 to monitor disease progression. Tissues were stained by picrosirius red, and collagen was quantified using ImageJ software.

Results: SGK1i ameliorated the progression to heart failure following TAC compared to the vehicle treated group, noted by a higher ejection fraction in the SGK1i groups compared to the vehicle group that is apparent even at day 21 (EF%: Sham 71.93, Vehicle 59.27, SGK1i A 70.66, SGK1i B 72.20) and is sustained through day 56 (EF%: Sham 70.50, Vehicle 49.87, SGK1i A 65.28, SGK1i B 64.22). In addition, parameters of LV structure were preserved in the SGK1i groups through the course of the study (LVESV mL Day 56: Sham 0.11, Vehicle 0.23, SGK1i A 0.13, SGK1i B 0.13). Morphometric measurements confirmed a significant increase in HW/BW in vehicle treated animals, which was mitigated by SGK1i. Hemodynamic studies confirmed the beneficial effects of SGK1i compared to vehicle treated animals (LVEDP, stroke work preserved, LV elastance better), with SGK1i groups not significantly different from sham animals. Finally, histological analysis demonstrated significantly less fibrosis and myofibrillar disarray in similar sections of SGK1i treated versus vehicle groups.

Conclusions: SGK1i prevented the development of TAC pressure overload-induced decline in systolic function, had beneficial effects on cardiac hypertrophy, and reduced fibrosis. These data support the continued development of SGK1 inhibitors as promising novel therapeutics for HF.